Nucleic Acids Research Advance Access originally published online on December 7, 2006
Nucleic Acids Research 2007 35(1):186-192; doi:10.1093/nar/gkl1038
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Nucleic Acids Research, 2007, Vol. 35, No. 1 186-192
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase
Department of Biochemistry and Molecular Genetics, University of Illinois Chicago 900 S. Ashland (M/C 669), Chicago, IL 60607, USA 1 Max Planck Institute for Biophysical Chemistry Am Fassberg 11 D-37077, Göttingen, Germany 2 SGX Pharmaceuticals Incorporation 10505 Roselle Street, San Diego, CA 92121, USA
*To whom correspondence should be addressed. Tel: +1 312 355 5029; Fax: +1 312 355 4535; Email: lavie{at}uic.edu
Received September 20, 2006. Revised October 26, 2006. Accepted November 7, 2006.
L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (–)-ß-2',3'-dideoxy-3'-thiacytidine (3TC)—an approved anti-human immunodeficiency virus (HIV) agent—and troxacitabine (TRO)—an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.
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